Pancreatic Cancer: Progress and Challenges in a Rapidly Moving Field

Eric A.Collisson and Kenneth P.Olive

Eric A. Collisson

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.Department of Medicine, University of California, San Francisco, San Francisco, California.

Introduction

The 2016 meeting made evident the development and maturation of the field of pancreatic cancer research. Prominent research topics now span the breadth of biomedical research disciplines and subfields, and individual projects have begun to leverage the synergy between these disciplines. Perhaps one of the most promising signs is that, despite the best efforts of session organizers, the topics covered by most speakers no longer fit neatly into the traditional silos of basic, translational, clinical, and epidemiologic research. Rare was the “basic science” talk that did not also explore how their findings might impact treatment, or clinical lecture that failed to explore the underlying biology of the disease. We see this trend as progress that should be fostered and have therefore organized this review around topical themes with summaries of selected speakers who are driving progress in each area.

Personalized Medicine

An overarching theme throughout the meeting was the drive to leverage specific molecular alterations in pancreatic tumors for therapeutic targeting. The opening Keynote lecture was delivered by Andrew Biankin of the University of Glasgow (Glasgow, United Kingdom). He focused on the science of stratification, laid out several methods of classifying the heterogeneity seen in pancreatic cancer patients, and shared the challenges his group had experienced executing precision medicine in pancreatic cancer due to the difficulties of tissue acquisition. He discussed the clinical relevance of a genomic scar detectable with whole-genome sequencing arising from germline or acquired defects in a handful of “BRCA” genes mediating homologous recombination (HR).

The clinical promise of targeting HR defects was further developed by Eileen O'Reilly from Memorial Sloan Kettering Cancer Center (MSKCC, New York, NY) in a second Keynote. She outlined the promising results her group is seeing using platinum agents with or without PARP inhibitors in patients with either a strong family history and/or known deleterious germline mutations in the BRCA1/2 or PALB2 genes. Significant and often durable responses were seen in the genetically defined group but not in those without an identified deleterious germline lesion. Dr. O'Reilly's team has launched a randomized trial examining the role that PARP inhibition plays in combination with platinum agents in germline-mutated patients. Nicholas Roberts from Johns Hopkins (Baltimore, MD) and Gloria Petersen from the Mayo Clinic (Rochester, MN) each discussed their work on inherited and environmental risks of pancreatic cancer. The ATM gene was found to have more premature truncating variants than expected, and a possible role for BUB1B was introduced by Dr. Roberts, while Dr. Petersen reinforced the deleterious effects of smoking and highlighted a protective role for aspirin in disease prevention.

Christine Iacobuzio-Donahue (MSKCC) discussed the evidence for and against heterogeneity between the primary tumor and daughter metastases seen in patients at autopsy. She presented detailed phylogenetic histories of multiple cases, showing effects potentially related to tumor stage as well as treatments such as chemotherapy. Manuel Hidalgo from Beth Israel Deaconess Hospital/Harvard (Boston, MA) presented his efforts to use patient-derived xenograft models to identify specific therapeutic sensitivities for individual pancreatic cancer patients. In particular, he focused on the promise of CDK4/6 inhibitors with taxanes and enhanced sensitivity of BRCA-mutant tumors to hypoxia-targeting agents. Carl Borrebaeck of Lund University (Lund, Sweden) presented his group's early detection efforts. Excitement in the room was palpable as he described an affordable, accurate, and sensitive serum-based assay capable of detecting stage I/II pancreatic cancer with 96% accuracy. Finally, Do-Young Oh (Seoul National University Hospital, Seoul, Republic of Korea) used molecular imaging, in the form of fluorodeoxyglucose PET, to predict response in patients treated with FOLFIRINOX, a standard first-line treatment in the metastatic setting. She found that early reduction in PET avidity was highly predictive of eventual clinical benefit and was informative after only 3 cycles of therapy, meaning patients might be quickly moved away from therapies to which they are not responding in a timely manner for second-line approaches.

It Is Not Just DNA Anymore

Several investigators presented data on their work looking beyond mutations in the genome to understand, classify, and eventually capitalize on heterogeneity in pancreatic cancer. Jen Jen Yeh (University of North Carolina at Chapel Hill, Chapel Hill, NC) and Kenneth Olive (Columbia University, New York, NY) each presented transcriptional (RNA-based) classifications of pancreatic cancer from virtually or physically microdissected cancer epithelium and stroma. Commonalities between the classifiers of different groups highlighted the distinctions between well and poorly differentiated tumor cells, as well as stromal subtypes related to inflammation and immune cell type, abundance, and activity. These data and ongoing efforts to utilize advanced computational techniques, such as network analysis, provide foundations both for basic science investigations and clinical correlates. In one such example, Robert Vonderheide (University of Pennsylvania, Philadelphia, PA) presented how immunologic signatures may predict immunotherapy benefit in pancreatic tumor gene expression data and how these associate with other molecular subtypes. Mara Sherman (Oregon Health Science University, Portland, OR) and Andrew Aguirre (Dana Farber Cancer Institute, Boston, MA) each presented data on the provocative roles that different metabolic pathways play in the genesis and maintenance of pancreatic cancer, possibly suggesting treatment approaches beyond the canonical kinase inhibitors and cytotoxic chemotherapy regimens.

Tumor Microenvironment: Cellular Diversity and Immuno-oncology

Investigators have been busy studying the contributions of stromal cells to pancreatic cancer biology, and this theme was well represented at the meeting. The consensus of many studies seems to be that, in addition to the classical modes of immune escape and checkpoint blockade that act in other cancers, the desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) exerts a local immunosuppressive effect that further hinders immune response. This immunosuppressive microenvironment has frustrated vaccine and checkpoint blockade approaches in PDAC to date. Several groups explored the roles of distinct cell types in facilitating local immunosuppression. Marina Pasca de Magliano (University of Michigan, Ann Arbor, MI), Jennifer Morton (Beatson Institute, Glasgow, United Kingdom), and Timothy Nywening (Washington University, St. Louis, WA) used genetic and pharmacologic approaches to explore the role that myeloid cells play in immunosuppression. Dr. Morton presented the striking finding that 20% of KPC mice, a well-validated preclinical model of pancreatic cancer, experience durable responses to the combination of CXCR2 inhibition and PD1 inhibition. Dafna Bar-Sagi (New York University, New York, NY) explored differences between pancreatic cancers arising in the head or tail of the pancreas, finding innate immune pathways that alter eosinophil influx, potentially affecting tumor growth and metastasis. Finally, Bernhard Renz (University of Munich, Munich, Germany) studied the impact of nerves in cancer, showing that stress-induced adrenergic signaling promotes tumor development and can be inhibited with β2-selective antagonists.

Genetic Pathways and Programs

The pancreatic cancer research field continues to explore the underlying biological programs of pancreatic cancer, but with an ever greater emphasis on translational potential. Ben Stanger (University of Pennsylvania) and Raghu Kalluri (MD Anderson Cancer Center, Houston, TX) both studied epithelial-to-mesenchymal transition (EMT) using sophisticated genetically engineered mouse models. Dr. Stanger found that there are different modes through which E-cadherin expression may be lost and that these are reflected in human molecular subtypes. Dr. Kalluri demonstrated that loss of EMT does not alter tumor development or metastasis, but influences chemosensitivity. Two groups also focused on the role of the p53 tumor suppressor in pancreatic cancer. Jennifer Baily (University of Texas Health Sciences, San Antonio, TX) found that mutant Kras-initiated neoplasia was suppressed by p53 in ductal cells but not acinar cells, and that loss of p53 enabled tumors to develop from ductal cells through a pancreatic intraepithelial neoplasia–independent pathway. Laura Attardi (Stanford University, Stanford, CA) used mouse models with artificial p53 mutations that selectively diminish or increase transactivation of subsets of genes to identify specific targets associated with pancreatic tumor suppression. This led to the identification of the non-receptor protein tyrosine phosphatase PTPN14 as a critical mediator of tumor suppression through negative regulation of YAP signaling. Sunil Hingorani (Fred Hutchinson Cancer Research Center, Seattle, WA) detailed the role of the Runx3 transcription factor in promoting metastatic spread through effects on cell-autonomous invasion and migration as well as on aspects of the tumor stroma. Iok In Christine Cho (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY) extended earlier work on reactive oxygen species, finding that Nrf2, an antioxidant protein upregulated by mutant Kras, helps to mediate cap-dependent translation. Finally, Channing Der (University of North Carolina at Chapel Hill) dissected the subtleties of signaling downstream of Ras in pancreatic cancer and made a strong case for the evaluation of potent ERK1/2 inhibitors and combination targeting of Ras effector pathways.

Philanthropy and Advocacy

The meeting also showcased the superb philanthropic support enjoyed by pancreatic cancer researchers and gave key philanthropic foundations an opportunity to meet, discuss their respective priorities, and share strategies and approaches. During the main meeting, Julie Fleshman of the Pancreatic Cancer Action Network announced the expansion of a personalized medicine program in pancreatic cancer called “Precision Promise.” Kerri Kaplan highlighted a prospective trial being supported by the Lustgarten Foundation for Pancreatic Cancer Research looking at immunotherapy in a small, but identifiable subset of patients with microsatellite unstable (MSI-high) pancreatic cancer. Finally, Dr. Allyson Ocean (Weill Cornell Medicine, New York, NY) introduced the Let's Win Foundation and its efforts to empower patients and their families. The coordination between different pancreatic cancer research and advocacy foundations will be a critical component of future successes in combatting this disease.

Success Factors: Benchmarks of Progress

Milestones we expect may be achieved in the 2 years before the next AACR pancreatic cancer meeting, anticipated in 2018 are of specific interest. These include successfully conducted biomarker-driven trials in PDAC and the first cracks in the immune fortress of PDAC. First, we expect that the great interest in personalized medicine will be actualized in the form of one or more national biomarker-driven clinical trials that link a molecular alteration with a specific targeted therapy. The phase III study of PEGPH20 in metastatic patients with high intratumoral hyaluronic acid is an exciting first step in this direction. We also strongly advocate for increased efforts to build large-scale, multi-site umbrella trials of personalized medicine approaches. Second, we expect that the extraordinary efforts to understand the interaction of the immune system with pancreatic cancer will yield concrete preclinical results extending the lifespan of autochthonous PDAC models, and that the first clinical responses to immunotherapy will be observed in human patients (even if sporadic); we note that such events presaged the breakthrough successes of immunotherapy in melanoma and other solid tumors. Third, we believe that for basic science progress to continue apace, immunocompetent, clinically predictive models must be made more widely available and easier to work with. David Tuveson (Cold Spring Harbor Laboratory) presented extensive validation of 3D organoid models that develop pancreatic cancer through a pancreatic intraepithelial neoplasia progression model following implantation into immunocompetent mice. We expect to learn of the continued development and validation of these models and of advanced models based on somatic editing that minimize the need for multiple genetically encoded alleles and that facilitate imaging of tumor development and progression. Finally, there is urgent need for consensus guidance on the screening and management of high-risk individuals identified through the increasing use of germline testing in cancer patients. We hope not to wait until the 2018 meeting for this, as patients and their families need advice today on how to integrate the explosion in molecular testing results into concrete advice for monitoring and potential treatment.

Challenges to the Pancreatic Cancer Research Community

Pancreatic cancer researchers need to prepare now for future challenges, and these were outlined at this meeting. Preclinical identification of new immunotherapy approaches call for new clinical assays to integrate immune-oncology into practice, including standardized immunodiagnostic technologies and accepted tissue biomarkers of antitumor immune activation (whether histopathologic, molecular, or ideally imaging based). Further consideration will also need to be given to the potential interactions (both positive and negative) between immune therapies and more general targeted therapeutics. With the emerging prominence of personalized medicine, the field must develop practical approaches to overcome the real operational challenges of implementing the approach in both community and academic medical centers alike. The wrap-up session highlighted the need to train professional “molecular oncologists,” whose clinical role would focus on the science of matching tumor and somatic alterations to specific therapeutic options. The dearth of such individuals across cancer today calls for new training avenues distinct from the typical clinical (trial driven) or laboratory-based (grant driven) algorithms familiar to academic centers today.

Conclusions

The 2016 AACR Special Meeting on Pancreatic Cancer updated the community on diverse areas of research and on the clinical efforts in progress around the world. We emerged from this year's meeting buoyed with optimism for the future of pancreatic cancer research and medicine. Real progress is being made as we converge upon consensus molecular subtypes, dominant mechanisms of immunosuppression, and penetrant germline risk factors. Looking forward, we expect that the intersection of these themes, how specific, cell-autonomous alterations and stromal cell types communicate with one another, will also bear fruit both intellectually and clinically. Emerging topics that we hope to hear more from next time include targeting of epigenetic deregulation and metabolic liabilities, especially given the progress being made in these areas in other malignancies. Although we have learned much, we have a long way to go in pancreatic cancer. The Orlando meeting both educated and energized us to get back to work!